Inhibitory synaptic transmission provided by inhibitory interneurons is essential both for the functioning of neuronal circuits and for normal brain development. The balance between inhibitory and excitatory synaptic transmission is critical for the proper wiring of brain circuits during early postnatal development. Alterations in the balance between inhibition and excitation have been found in many neurodevelopmental and neuropsychiatric disorders, including autism, Down Syndrome, Fragile X Syndrome, and schizophrenia. The balance between excitation and inhibition is not static, but is dynamically changed during different patterns of stimulation by short-term plasticity. The strengths of both excitation and inhibition are modulated by short-term plasticity, and differences in short-term plasticity between these two components causes the balance of excitation to inhibition to be frequency-dependent. In hippocampus, GABAergic interneurons provide powerful inhibition to the excitatory pyramidal cells that is vital to prevent epilepsy and excitotoxicity. In addition, hippocampal interneurons can synchronize the firing of pyramidal cells and drive population oscillations that are essential for learning and memory. Hippocampal interneurons are highly diverse in their anatomical, neurochemical, and physiological properties. Knowledge of the physiological properties and functional roles of these different interneuron subtypes, although required for understanding the relationship between hippocampal circuit function and behavior in both normal and disease states, is still limited. In the CA1 region of hippocampus, feedforward inhibition is provided through two pathways, the Schaffer collateral (SC) pathway onto interneurons in stratum radiatum (SR), and the temporoammonic (TA) pathway onto interneurons in stratum lacunosum-moleculare (SLM). However, the little is known about the frequency-dependence of feed-forward inhibition and how it affects the balance of excitation to inhibition. In this proposal we will test the mechanisms, functional effects, and consequences for circuit function of short-term plasticity of feed-forward inhibition onto CA1 pyramidal cells from both the SC and TA pathways. Together these data will provide information that is essential to understanding how the balance of excitation and inhibition is regulated, how short-term plasticity helps gate the flow of information through hippocampus, and the normal functional roles of different interneuron subtypes. This information may provide potential therapeutic targets for selectively modifying inhibition in neurological disease, as well as providing a foundation for future studies investigating the role of short-term plasticity of feed-forward inhibition in neuropsychiatric disorders and neurodevelopmental disorders that cause mental retardation.